Abstract

Background: The aim of the present study was to investigate the association of fMRI blood oxygen–level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD).

Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing.

Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation.

Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn.

Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.

Acknowledgements: The authors thank Lyndall Schumann for proofreading the manuscript. L. Booij is supported by a New Investigator Award from the Canadian Institutes of Health Research (CIHR). The DNA methylation analyses were funded by grants from the Fonds de Recherche en Santé — Québec and a Brain, Behavior Research Foundation-NARSAD Young Investigator Award awarded to L. Booij. The clinical part of the study with patient recruitment, neuroimaging and genetic data analysis was supported by Science Foundation Ireland (SFI, G20330) within a Stokes Professorship grant and by the European Union with a Marie Currie International Training Network grant (rBirth) to T. Frodl.